Volume 21, Issue 1 (January 2023)                   IJRM 2023, 21(1): 33-42 | Back to browse issues page

XML Persian Abstract Print

Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Vaziri Nezamdoust F, Hadinedoushan H, Ghasemi N. Association of cytotoxic T-lymphocyte-associated protein 4 polymorphisms with recurrent pregnancy loss: A case-control study. IJRM 2023; 21 (1) :33-42
URL: http://ijrm.ir/article-1-2118-en.html
1- Reproductive Immunology Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
2- Reproductive Immunology Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. , hhadin@ssu.ac.ir
3- Abortion Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Abstract:   (779 Views)
Background: A large proportion of cases of recurrent pregnancy loss (RPL) are associated with immunological factors.
Objective: This study investigated the association between single nucleotide polymorphisms of cytotoxic T-lymphocyte-associated protein (CTLA)-4 gene in women with a history of RPL compared to healthy women.
Materials and Methods: A case-control study was performed on 2 groups consisting of 120 healthy women with no history of abortion and at least one delivery (control) and 120 women with a history of 2 or more primary RPLs (case). In addition, 5 mL of peripheral blood sample was taken from all subjects. The frequencies of CTLA-4 rs3087243 and rs231775 polymorphisms were assayed by restriction fragment length polymorphism polymerase chain reaction and rs5742909 using the high-resolution melting real-time polymerase chain reactionmethod.
Results: The mean age of the women in the control and RPL groups were 30.03 ± 4.23 (range 21-37), and 28.64 ± 3.61 yr (range 20-35), respectively. Pregnancy loss numbers ranged between 2-6 in women with a history of RPL, and between 1 and 4 in the successful pregnancy group. Statistical analysis showed a significant difference between the genotypes of GG and AG in the 2 groups in rs3087243 polymorphism (OR 1.00 for GG genotype and OR 2.87 for AG genotype, p = 0.0043). No significant difference was observed in the genotype frequencies of rs231775 and rs5742909 polymorphisms, of the 2 groups (p = 0.37, and p = 0.095), respectively.
Conclusion: Our findings indicated that CTLA-4 polymorphism, rs3087243, might be associated with a risk of RPL in Iranian women.
Full-Text [PDF 1211 kb]   (658 Downloads) |   |   Full-Text (HTML)  (67 Views)  
Type of Study: Original Article | Subject: Reproductive Genetics

1. Walker MH, Tobler KJ. Female Infertility. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022.
2. Chernyshov VP, Sudoma IO, Dons' koi BV, Kostyuchyk AA, Masliy YV. Elevated NK cell cytotoxicity, CD158a expression in NK cells and activated T lymphocytes in peripheral blood of women with IVF failures. Am J Reprod Immunol 2010; 64: 58-67. [DOI:10.1111/j.1600-0897.2010.00825.x] [PMID]
3. Hanzlikova J, Ulcova‐Gallova Z, Malkusova I, Sefrna F, Panzner P. TH1-TH2 response and the atopy risk in patients with reproduction failure. Am J Reprod Immunol 2009; 61: 213-220. [DOI:10.1111/j.1600-0897.2009.00683.x] [PMID]
4. Chaithra PT, Malini SS, Kumar CSh. An overview of genetic and molecular factors responsible for recurrent pregnancy loss. Int J Hum Genet 2011; 11: 217-225. [DOI:10.1080/09723757.2011.11886145]
5. van Dijk MM, Kolte AM, Limpens J, Kirk E, Quenby S, van Wely M, et al. Recurrent pregnancy loss: Diagnostic workup after two or three pregnancy losses? A systematic review of the literature and meta-analysis. Hum Reprod Update 2020; 26: 356-367. [DOI:10.1093/humupd/dmz048] [PMID] [PMCID]
6. Brassard M, AinMelk Y, Baillargeon J-P. Basic infertility including polycystic ovary syndrome. Med Clin North Am 2008; 92: 1163-1192. [DOI:10.1016/j.mcna.2008.04.008] [PMID]
7. Carrington B, Sacks G, Regan L. Recurrent miscarriage: Pathophysiology and outcome. Curr Opin Obstet Gynecol 2005; 17: 591-597. [DOI:10.1097/01.gco.0000194112.86051.26] [PMID]
8. Harris LH, Grossman D. Complications of unsafe and self-managed abortion. N Engl J Med 2020; 382: 1029-1040. [DOI:10.1056/NEJMra1908412] [PMID]
9. Li Y, Yu Sh, Huang Ch, Lian R, Chen C, Liu S, et al. Evaluation of peripheral and uterine immune status of chronic endometritis in patients with recurrent reproductive failure. Fertil Steril 2020; 113: 187-196. [DOI:10.1016/j.fertnstert.2019.09.001] [PMID]
10. Kaser D. The status of genetic screening in recurrent pregnancy loss. Obstet Gynecol Clin 2018; 45: 143-154. [DOI:10.1016/j.ogc.2017.10.007] [PMID]
11. Hadinedoushan H, Mirahmadian M, Aflatoonian A, Akbari F, Hatmi N. Cytokine production by peripheral blood mononuclear cells in recurrent miscarriage. Cytokine 2004; 28: 83-86. [DOI:10.1016/j.cyto.2004.07.002] [PMID]
12. Wang X, Lin Q, Ma Z, Hong Y, Zhao A, Di W, et al. Association of the A/G polymorphism at position 49 in exon 1 of CTLA‐4 with the susceptibility to unexplained recurrent spontaneous abortion in the Chinese population. Am J Reprod Immunol 2005; 53: 100-105. [DOI:10.1111/j.1600-0897.2004.00251.x] [PMID]
13. Kaufman KA, Bowen JA, Tsai AF, Bluestone JA, Hunt JS, Ober C. The CTLA-4 gene is expressed in placental fibroblasts. Mol Hum Reprod 1999; 5: 84-87. [DOI:10.1093/molehr/5.1.84] [PMID]
14. Song Y, Chen Y, Xu Q. Association among cytotoxic T-lymphocyte antigen 4 gene, rs231775 polymorphism, and recurrent pregnancy loss risk. Biosci Rep 2019; 39: BSR20181760. [DOI:10.1042/BSR20181760] [PMID] [PMCID]
15. Li L, Liu J, Qin S, Li R. Correlation between CTLA4 genetic polymorphisms, its serum protein level and the susceptibility to recurrent spontaneous abortion: A case-control study. Medicine 2018; 97: e12754. [DOI:10.1097/MD.0000000000012754] [PMID] [PMCID]
16. Alijotas-Reig J, Llurba E, Gris JM. Potentiating maternal immune tolerance in pregnancy: A new challenging role for regulatory T cells. Placenta 2014; 35: 241-248. [DOI:10.1016/j.placenta.2014.02.004] [PMID]
17. Dai Zh, Tian T, Wang M, Liu X, Lin S, Yang P, et al. CTLA-4 polymorphisms associate with breast cancer susceptibility in Asians: A meta-analysis. Peer J 2017; 5: e2815. [DOI:10.7717/peerj.2815] [PMID] [PMCID]
18. Crossa J. Methodologies for estimating the sample size required for genetic conservation of outbreeding crops. Theor Appl Genet 1989; 77: 153-161. [DOI:10.1007/BF00266180] [PMID]
19. Hong EP, Park JW. Sample size and statistical power calculation in genetic association studies. Genomics Inform 2012; 10: 117-122. [DOI:10.5808/GI.2012.10.2.117] [PMID] [PMCID]
20. Cargnin S, Galli U, Shin JI, Terrazzino S. CTLA-4 rs231775 and risk of acute renal graft rejection: An updated meta-analysis with trial sequential analysis. Sci Rep 2020; 10: 12850. [DOI:10.1038/s41598-020-69849-4] [PMID] [PMCID]
21. Tu Y, Fan G, Dai Y, Zeng T, Xiao F, Chen L, et al. Association between rs3087243 and rs231775 polymorphism within the cytotoxic T-lymphocyte antigen 4 gene and Graves' disease: A case/control study combined with meta-analyses. Oncotarget 2017; 8: 110614-110624. [DOI:10.18632/oncotarget.22702] [PMID] [PMCID]
22. Hadinedoushan H, Abbasirad N, Aflatoonian A, Eslami G. The serum level of transforming growth factor beta1 and its association with Foxp3 gene polymorphism in Iranian women with recurrent spontaneous abortion. Hum Fertil 2015; 18: 54-59. [DOI:10.3109/14647273.2014.927594] [PMID]
23. Najafi S, Hadinedoushan H, Eslami G, Aflatoonian A. Association of IL-17A and IL-17 F gene polymorphisms with recurrent pregnancy loss in Iranian women. J Assist Reprod Genet 2014; 31: 1491-1496. [DOI:10.1007/s10815-014-0294-0] [PMID] [PMCID]
24. Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, et al. Trans-endocytosis of CD80 and CD86: A molecular basis for the cell-extrinsic function of CTLA-4. Science 2011; 332: 600-603. [DOI:10.1126/science.1202947] [PMID] [PMCID]
25. Alegre ML, Shiels H, Thompson CB, Gajewski TF. Expression and function of CTLA-4 in Th1 and Th2 cells. J Immunol 1998; 161: 3347-3356. [DOI:10.4049/jimmunol.161.7.3347]
26. Jin LP, Fan DX, Zhang T, Guo PF, Li DJ. The costimulatory signal upregulation is associated with Th1 bias at the maternal-fetal interface in human miscarriage. Am J Reprod Immunol 2011; 66: 270-278. [DOI:10.1111/j.1600-0897.2011.00997.x] [PMID]
27. Ding J-L, Diao L-H, Yin T-L, Huang C-Y, Yin B, Chen C, et al. Aberrant expressions of endometrial Id3 and CTLA‐4 are associated with unexplained repeated implantation failure and recurrent miscarriage. Am J Reprod Immunol 2017; 78: e12632. [DOI:10.1111/aji.12632] [PMID]
28. Fan Q, Zhang J, Cui Y, Wang C, Xie Y, Wang Q, et al. The synergic effects of CTLA-4/Foxp3-related genotypes and chromosomal aberrations on the risk of recurrent spontaneous abortion among a Chinese Han population. J Hum Genet 2018; 63: 579-587. [DOI:10.1038/s10038-018-0414-2] [PMID] [PMCID]
29. Pendeloski KPT, Sass N, Torloni MR, Mattar R, Moron AF, Franchim CS, et al. Immunoregulatory gene polymorphisms in women with preeclampsia. Hypertens Res 2011; 34: 384-388. [DOI:10.1038/hr.2010.247] [PMID]
30. Zhou L, Cheng L, He Y, Gu Y, Wang Y, Wang C. Association of gene polymorphisms of FV, FII, MTHFR, SERPINE1, CTLA4, IL10, and TNFalpha with pre-eclampsia in Chinese women. Inflamm Res 2016; 65: 717-724. [DOI:10.1007/s00011-016-0953-y] [PMID]
31. Misra MK, Mishra A, Phadke SR, Agrawal S. Association of functional genetic variants of CTLA4 with reduced serum CTLA4 protein levels and increased risk of idiopathic recurrent miscarriages. Fertil Steril 2016; 106: 1115-1123. [DOI:10.1016/j.fertnstert.2016.06.011] [PMID]
32. Bonyadi M, Parsa S, Taghavi S, Zeinalzadeh N. Association study of CTLA-4+ 49A/G gene polymorphism with recurrentpregnancy loss in the Iranian Azeri Turkish ethnic group. Turk J Med Sci 2017; 47: 778-781. [DOI:10.3906/sag-1511-67] [PMID]
33. Jääskeläinen E, Toivonen S, Keski-Nisula L, Paattiniemi E-L, Helisalmi S, Punnonen K, et al. CTLA-4 polymorphism 49A-G is associated with placental abruption and preeclampsia in Finnish women. Clin Chem Lab Med 2008; 46: 169-173. [DOI:10.1515/CCLM.2008.034] [PMID]
34. Lerner T, Bianco B, Teles J, Vilarino F, Christofolini D, Barbosa C. Analysis of CTLA4 gene variant in infertile Brazilian women with and without endometriosis. Int J Immunogenet 2011; 38: 259-262. [DOI:10.1111/j.1744-313X.2011.01000.x] [PMID]
35. Su J, Li Y, Su G, Wang J, Qiu T, Ma R, et al. Genetic association of CTLA4 gene with polycystic ovary syndrome in the Chinese Han population. Medicine 2018; 97: e11422. [DOI:10.1097/MD.0000000000011422] [PMID] [PMCID]
36. Devaraju P, Gulati R, Singh B, Mithun C, Negi V. The CTLA4+ 49 A/G (rs231775) polymorphism influences susceptibility to SLE in South Indian Tamils. Tissue Antigens 2014; 83: 418-421. [DOI:10.1111/tan.12363] [PMID]
37. Ahmed S, Ihara K, Kanemitsu S, Nakashima H, Otsuka T, Tsuzaka K, et al. Association of CTLA‐4 but not CD28 gene polymorphisms with systemic lupus erythematosus in the Japanese population. Rheumatology 2001; 40: 662-667. [DOI:10.1093/rheumatology/40.6.662] [PMID]
38. Tang M-J, Zhou Z-B. Association of the CTLA-4+ 49A/G polymorphism with rheumatoid arthritis in Chinese Han population. Mol Biol Rep 2013; 40: 2627-2631. [DOI:10.1007/s11033-012-2349-6] [PMID]
39. Chaouali M, Carvalho A, Tezeghdenti A, Azaiez MB, Cunha C, Ghazouani E, et al. Cytotoxic T lymphocyte antigen-4 gene polymorphisms and susceptibility to type 1 autoimmune hepatitis in the Tunisian population. Genes Dis 2018; 5: 256-262. [DOI:10.1016/j.gendis.2017.12.006] [PMID] [PMCID]

Send email to the article author

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Designed & Developed by : Yektaweb